title: Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases.
abstract: BACKGROUND
  Molecular biomarkers offer the potential for refining prognostic determinants in patients undergoing cancer surgery. Among patients with colorectal cancer, KRAS and BRAF are important biomarkers, but their role in patients undergoing surgical therapy for liver metastases is unknown. In this study, the incidence and prognostic significance of KRAS and BRAF mutations were determined in patients undergoing surgical therapy of colorectal liver metastases (CRLM).
  
  
  METHODS
  KRAS and BRAF analysis was performed on 202 patients undergoing surgery for CRLM between 2003 and 2008. Tumor samples were analyzed for somatic mutations using sequencing analysis (KRAS, codon12/13, BRAF, V600E). The frequency of mutations was ascertained, and their impact on outcome was determined relative to other clinicopathologic factors.
  
  
  RESULTS
  KRAS gene mutations were detected in 58/202 patients (29%). In contrast, mutation in the BRAF gene was identified in very low frequency in this surgical cohort, found in only 4/202 (2%) patients. On multivariate analysis, KRAS mutation was associated with worse survival (hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.21-3.26), as well as recurrence risk (HR, 1.68; 95% CI, 1.04-2.70). Although other clinicopathologic features, including tumor number, carcinoembryonic antigen, and primary stage were also associated with survival, KRAS status remained independently predictive of outcome. The low incidence of BRAF mutation limited assessment of its prognostic impact.
  
  
  CONCLUSIONS
  Whereas KRAS mutations were found in approximately one third of patients, BFAF mutations were found in only 2% of patients undergoing surgery for CRLM. KRAS status was an independent predictor of overall and recurrence-free survival. Molecular biomarkers such as KRAS may help to refine our prognostic assessment of patients undergoing surgical therapy for CRLM.
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Georgios
authors.initials: G
authors.lastname: Karagkounis
authors.forename: Michael S
authors.initials: MS
authors.lastname: Torbenson
authors.forename: Hubert D
authors.initials: HD
authors.lastname: Daniel
authors.forename: Nilofer S
authors.initials: NS
authors.lastname: Azad
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Ross C
authors.initials: RC
authors.lastname: Donehower
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hirose
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Pawlik
authors.forename: Michael A
authors.initials: MA
authors.lastname: Choti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis*; D015179:Colorectal Neoplasms / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality* / Q000556:secondary / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: D015415:Biomarkers; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: factors; hepatectomy; molecular; personalized therapy; predictors